[unreadable] [unreadable] Skin cancer is the most common type of skin cancer in the United States. There are two broad categories of skin cancer, non-melanoma type that include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) and malignant melanoma. BCC and SCC are associated with significant morbidity amongst adult populations. On the other hand, melanoma is associated with about 7,910 deaths per year in the United States and the American Cancer Society estimates that there will be 62,190 new cases of melanoma in 2006 in the US alone. Better strategies are needed to identify individuals in the US population at risk for skin cancer, in particular melanoma which can be curable if diagnosed early. Nitric oxide (NO) is a gas that is produced in various cells of the body. This gas is synthesized from an amino acid L-arginine by a group of enzymes called nitric oxide synthases (NOS), i.e. endothelial (e), inducible (i), and neuronal (n)NOS. Because of the difficulty in detecting short-lived NO in gaseous form, expression of the NOS enzymes is commonly used as a surrogate for NO production. There is considerable evidence in the literature to implicate variable expression of NOS in skin cancer. NO is also important in mediating the effects of ultraviolet radiation on the skin such as with sun exposure. Also, differential expression of NOS has been associated with progression of melanoma. Interestingly, NOS enzymes are highly expressed in SCC tissue whereas they are down-regulated in BCC specimens. Most of the work in skin cancer thus far has focused on somatic changes in cancer tissue to evaluate the association with cancer progression or mortality. This application uses unique resources in a nested case-control study within the well-characterized Nurses' Health Study at the Channing Laboratory, Brigham and Women's Hospital to evaluate the hypothesis that NOS gene variants may be associated with a risk for skin cancer. This specific aims of this application include evaluation of polymorphisms with functional relevance and haplotypes of the three NOS genes in relation to risk for melanoma, SCC and BCC and to investigate associations between these NOS variants and risk factors for skin cancer (number of sunburns, mole counts, ability-to-tan and susceptibility-to-burn). A major strength of this application is the simultaneous evaluation of SCC, BCC and melanoma in the same population-based cohort of women where majority of the data on skin cancer risk factors was collected prior to the diagnosis of skin cancer. Most important, as nitric oxide production can be modified by using topical agents to increase or decrease production locally in the skin, future chemoprevention strategies may be developed based on results of this work. [unreadable] [unreadable] [unreadable]